Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward. This Review summarizes adaptive immune cell dysregulation in obesity and type 2 diabetes mellitus (T2DM). Under-appreciated comorbidities of obesity and T2DM (oral cavity inflammation, neuroinflammation and dysbiosis) are considered, and previous clinical trials of anti-inflammatory therapies for T2DM are discussed. Key points Although obesity and/or T2DM are widely known as metabolic diseases, the development of the field of meta-inflammation has demonstrated the strong immune component of both conditions. An appropriate balance between T helper 17 cells and regulatory T cells, and effector and regulatory B cells, is essential to maintain local immunity during systemic inflammation, especially in obesity and in its associated comorbidities. Clinical trials targeting inflammatory mediators of obesity and T2DM (such as IL-1β and tumour necrosis factor) to improve glycaemic control in T2DM have shown only mo